Recent developments provide strong support for the role of plasma lipoproteins in atherosclerotic plaque formation. The aim of this proposal is to study the minimal structural features of human apo A-I (HuA-I) that inhibit and/or reverse atherosclerosis. Using as a working hypothesis that the amphipathic helical motif is the predominant structural and functional domain in apo A-I, we have begun animal experiments using model amphipathic helical peptide analogs to define those minimal structural features. We have obtained exciting preliminary data indicating that peptide mimics of human apo A-I (HuA-I) inhibit diet-induced foam cell formation in mice, and spontaneous lesion formation that is known to take place in mice lacking the apo E gene. The present proposal will test this hypothesis further in peptide or mutant apo A-I transgenic and in apo E knockout mice via the following specific aims: 1. Studies of atherosclerosis protection by model amphipathic helical peptides. a. Intraperitoneal injection or transgenic expression in diet-sensitive mice that form lipid-rich foam cell lesions. b. Peptide intraperitoneal administration or expression of peptide transgenes in mice lacking the apo E gene will be done to study the ability of peptide to inhibit fibrous lesions. 2. Studies of site- directed mutants of human apolipoprotein A-I. a. Design and study of apo A-I mutants. b. Expression of well-characterized apo A-I mutants in transgenic mouse models.